title: BCL2 and BCLxL are key determinants of resistance to antitubulin chemotherapeutics in melanoma cells.
abstract: Malignant melanoma is refractory to various chemotherapeutics including antitubulin agents such as paclitaxel. Previous studies have suggested a link between βIII-tubulin overexpression and paclitaxel resistance through alterations in the properties of the mitotic spindle. We found that paclitaxel treatment induced temporary mitotic arrest in 7 melanoma cell lines irrespective of the βIII-tubulin level, suggesting that βIII-tubulin had no significant influence on spindle properties. On the other hand, the amount of BCL2, an anti-apoptotic protein, was well correlated with paclitaxel resistance. Treatment of the paclitaxel-resistant cell lines with ABT-737, an inhibitor of BCL2 and BCLxL, or simultaneous knock-down of BCL2 and BCLxL dramatically increased the cells' sensitivity, while knock-down of MCL1, another member of the BCL2 family, had only a minimal effect. Our results suggest that the paclitaxel sensitivity of melanoma cells is attributable to apoptosis susceptibility rather than a change in spindle properties and that BCL2 and BCLxL play a pivotal role in the former.
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Sciences, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Watanabe
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuhira
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Shuya
authors.initials: S
authors.lastname: Kasai
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shibazaki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Toshihide
authors.initials: T
authors.lastname: Akasaka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Masuda
authors.forename: Chihaya
authors.initials: C
authors.lastname: Maesawa
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000737:chemistry; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008545:Melanoma / Q000737:chemistry / Q000378:metabolism*; D009596:Nitrophenols / Q000737:chemistry; D017239:Paclitaxel / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry; D014404:Tubulin / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: C501332:ABT-737; D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; C498585:TUBB3 protein, human; D014404:Tubulin; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases; C506433:CASP9 protein, human; D053453:Caspase 9; D017239:Paclitaxel
keywords: BCL2; BCLxL; apoptosis; melanoma; paclitaxel